The present invention is for the use of certain 3-alkyloxy-, aryloxy-, or arylalkyloxybenzo[b]-thiophene-2-carboxamides, and pharmaceutically acceptable salts thereof, to prevent the adhesion of leukocytes to endothelial cells. Leukocyte adherence to vascular endothelium is integral to the pathogenesis of inflammation. The adhesion process precedes transendothelial migration of leukocytes into surrounding tissue and ensuing tissue damage. Compounds that can block this initial adhesive interaction are expected to have efficacy in the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, and psoriasis. Other indications would include but are not limited to adult respiratory distress syndrome, reperfusion injury, ischemia, ulcerative colitis, vasculitides, atherosclerosis, inflammatory bowel disease, and tumor metastases.
Adhesion receptors are organized into three main families: the selectins, the immunoglobulin superfamily, and the integrins (Nature 1990;346:426). Members of all three classes are involved in mediating leukocyte adhesion during inflammation (for reviews of this area see: Thrombosis and Hemostasis 1991;65(3):223), Clinical and Experimental Allergy 1990;20:619, Transplantation 1989;48:727, Biochemical Pharm. 1990;40(8):1683). Endothelial leukocyte adhesion molecule-1 (ELAM-1 or E-selectin) is a member of the selectin family of glycoproteins that promote cell-cell adhesion. ELAM-1 is reported to be maximally expressed on the surface of endothelial cells 4 hours after stimulation of the endothelial cells with cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor .alpha. (TNF-.alpha.) or other inflammatory mediators, such as lipopolysaccharide (LPS) (Pro. Nat. Acad. Sci. 1987;84:9238).
Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily. It is also upregulated with maximum expression occurring 12 to 24 hours after stimulus. It has been shown that 4 hours after the endothelial cells are stimulated with an inflammatory mediator, both ELAM-1 and ICAM-1 are present on the cell surface (J. Clin. Invest. 1988;82:1746 and J. Immun, 1986;137:1893, Blood 1991;78:2721).
The 3-alkyloxy-, aryloxy-, and arylalkyloxybenzo[b]thiophene-2-carboxamides of the present invention have been shown in an in vitro assay to prevent the adhesion of neutrophils to human umbilical vein endothelial cells (HUVECS) stimulated with TNF.alpha..
The 3-alkyloxy-, aryloxy-, and arylalkyloxybenzo[b]thiophene-2-carboxamides of the present invention are new but are included in the generic scope of U.S. Pat. No. 4,800,211 as possible dual inhibitors of cyclooxygenase and 5-lipoxygenase. The specific compounds of the present invention do not significantly inhibit isolated 5-lipoxygenase.